Abstract Pneumonia is a major health concern. The most frequent cause of pneumonia is the pneumococcus Streptococcus pneumoniae, which in addition causes otitis media, septicemia, empyema, meningitis, and other diseases. While the morbidity and mortality of pneumococcal infections is emphasized, disease is in actuality an exceptional event. Most pneumococcal interactions with humans are sub-clinical. We need a better understanding of which host-pathogen interactions determine whether pneumococcal infection causes disease. Our ongoing screening of community isolates reveals that pneumococci vary in stimulating divergent pathways in macrophages that enhance either (i) rapid cytokine expression and lung defense, or (ii) programmed necrosis and lung infection. Preliminary data relevant to these divergent outcomes lead us to postulate that the detrimental pathway is triggered by high levels of cyclic di-AMP, is advanced by necrosome kinases, and is inhibited by NF-?B-mediated gene transcription. Our central hypothesis is that virulent pneumococci induce macrophage necroptosis unless inhibited by NF-?B, to be tested in 3 specific aims: 1) Determine whether necroptosis is the programmed necrosis pathway induced by pneumococci, distinguishing more virulent strains. We will test whether pneumococci that stimulate programmed necrosis cause more severe infection, whether this programmed necrosis is necroptosis specifically, and whether necrosome inhibitors can improve pneumonia. 2 Determine whether macrophage NF-?B inhibits pneumococcus-induced programmed necrosis. We will test whether the amount of NF-?B activation dictates the potential for pneumococci to induce programmed necrosis, whether exogenous triggering of NF-?B can be helpful, and which protective pathways NF-?B induces. 3) Determine whether pneumococcal cyclic di-AMP drives programmed necrosis in macrophages. We will test whether cyclic di-AMP variation amongst pneumococci in the community differentiates those that activate NF-?B vs. necrosis, whether cyclic di-AMP dictates whether or not pneumococcus induces necrosis and causes severe pneumonia, whether STING drives pneumonia severity from virulent pneumococci, and what besides cyclic di-AMP content distinguishes pneumococcal isolates that drive divergent responses. Determining which factors tip the balances and drive macrophages towards beneficial NF-?B vs. detrimental necroptosis outcomes will add to our understanding of pneumonia immunology, microbiology, infectious disease, and pulmonary pathophysiology. In addition, these studies have translational implications. Future research may incorporate pathways here elucidated into pneumococcal surveillance programs and vaccine development research. More directly, activating or inhibiting (respectively) the beneficial or detrimental pathways elucidated here may redirect macrophage-pneumococcal interactions and help prevent or cure pneumonias, which will begin to be addressed in the proposed studies.